validation by Kailash Vilegave

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Analytical test procedures Instrument calibration Critical support system Operators Raw materials Packaging materials Equipment Facilities Manufacturing process Product design Utilities & services Records & reports

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VALIDATION OF TABLET & PARENTERAL:

VALIDATION OF TABLET & PARENTERAL PRESENTED BY……. Mr. Kailash Vilegave Department Of Pharmaceutics Shivajirao S . Jondhle college of pharmacy Asangaon 421601 1

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Contents Introduction General aspects Validation of parenterals Validation of tablets References 2

INTRODUCTION :

INTRODUCTION DEFINITION Validation is attaining & documentation of sufficient evidence to give reasonable assurance, stating that equipment or process does & will do what it purports to do. According to US FDA “ validation is establishing documented evidence which provides a higher degree of assurance that a specific process , equipment or facility meets its pre determined specifications & quality characteristics & will consistently produce a product of standard quality” 3

REASONS FOR VALIDATION:

REASONS FOR VALIDATION Objective : to manufacture product of requisite quality with low cost Govt regulation Assurance of quality Cost reduction 4

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WHEN VALIDATION BEGINS Validation should begin in the designing stage for new facility & pre formulation stage for a new dosage form . WHO DOES In order to have a valid & qualified system it must be designed by qualified individuals only. As it is complex process, it is performed by individuals with necessary training & experience & who are themselves previously qualified. 5

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6 Validation team

FUNCTION OF DIFFERENT DEPARTMENTS:

FUNCTION OF DIFFERENT DEPARTMENTS Engineering Install, qualify & certify plant facility, equipment &support systems. R & D Design, optimize, qualify manufacturing process with limits & specifications. Manufacturing Operate & maintain plant facilities, equipments ,support systems, process and strictly follow SOP. Q.C Follow the validation protocol develop by Q.A & validate the incoming stock ,in process critical system &final product. Q.A Establish approvable validation protocols &conduct process validation by monitoring ,sampling ,challenging the process & equipment. 7

VALIDATION PRIORITY:

VALIDATION PRIORITY Large volume parenteral. Small volume parenteral. Ophthalmic, other sterile products & medical devices. 8

Component of validation:

Component of validation Analytical test procedures Instrument calibration Critical support system Operators Raw materials Packaging materials Equipment Facilities Manufacturing process Product design Utilities & services Records & reports 9 validation

Types of validation:

Types of validation Prospective validation. Retrospective validation. Concurrent validation. revalidation. Prospective validation This is validation program executed before commercialization of a new drug/ formulation, to make sure that there are no potential hazards in full scale manufacture of product. 10

Retrospective validation:

Retrospective validation It is a program chosen for established products whose manufacturing process are considered stable (i.e. long history of state control operation). This method involves statistical analysis of numerical data obtained from different batches & then justify whether the system is qualified or not. The data includes MFR,BFR. b) assay values. End product test results. In process data. 11

Retrospective validation:

Retrospective validation Different parameters checked in parenteral . pH value . Viscosity. Density. Color & clarity. Potency. Sterilization parameters. Different statistical methods are Basic statistics (mean , standard deviation, tolerance limit ) . Analysis of variance (ANOVA) . Regression analysis. Cumulative sum analysis. Control charting – most advance & useful. 12

Concurrent validation:

Concurrent validation This method includes in process monitoring of critical process steps & end product testing of current production along with documentation . This shows that the manufacturing is in state of control The same parameter of retrospective validation are evaluated with more stress on critical parameters affecting the process . Revalidation This method involves validation of facility which is previously validated when Change in critical component . Change in critical piece of equipment. Change in facility / plant (design / location ). Significant increased / decease in batch size. Sequential batches fail to meet product / process specifications 13

Validation of parenteral:

Validation of parenteral Design & validation of facility There are four basic steps in validation of facility Planning Documentation Construction Testing 14

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Planning Site selection Design staff Material flow path Room layout 15

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Material flow path 16 Receiving stores Component preparation Aseptic filling capping inspection labeling quarantine Release shipping

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Typical room layout: Salient feature Double door with interlock system Positive pressure in sterile area. Separate entry for material &personal. Clean room or class-100 room in the filling area. Entry is done only after gowning 17

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3. Construction Steps involved are: Ground Shell Rooms sewers Ductwork Landscaping 18

Calibration &certification:

Calibration &certification Its done for Sensitivity 2. Accuracy 3. precision 19

Support system:

Support system Air system Validation is performed mainly in four phases Pre construction phase - - design &engineer air system Construction phase - - all steps of planning are in place Post Construction phase - - rest phase Post Construction phase - - same test are performed with machines HVAC system Purpose -To provide a specific set of environmental conditions required for manufacturing process. 20

AIR SYSTEM:

AIR SYSTEM 21 AIR FILTRATION CONTROL SYSTEM

Clean Room :

Clean Room Class-100 room : particle count limit 100/cubic foot of 0.5 µm or larger in size. Class- 10,000 room : particle count limit 10,0000/cubic foot of 0.5 µm or larger in size 22 Area Absolute Intermediate Pre-filter preparation optional recommended recommended washing optional recommended recommended filling required optional recommended packaging not required not recommended recommended

ENVIRONMENT PERFORMANCE TESTS:

ENVIRONMENT PERFORMANCE TESTS Hepa filter leak test . Temperature control test. Humidity control test. Air flow uniformity test. Pressure control test. Particle count test. Induction leak test. Airborne microbial sampling. 23

VALIDATION OF WATER SYSTEM:

VALIDATION OF WATER SYSTEM Different classes of water CLASS MINERAL MICROBES T.M.REMOVAL PYROGEN QUALITY WELL WATER + + - + I POTABLE + CONTROL - + II PURIFIED - CONTROL - + III W.F.RINSE - CONTROL + NIL IV W.F.I - NIL + NIL V 24

Water sampling and testing:

Water sampling and testing SAMPLE POINT TEST FREQUENCY RAW WATER MICROBIAL, cl RESIDUAL, TDS,PH DAILY FILTERS MICROBIAL, cl RESIDUAL DAILY DISTILLATION /R.O EQUIPEMENT MICROBIAL ,pH CONTINUOUS STORAGE TANK MICROBIAL, p H, PYROGEN, CHEMICALS USP. MULTIPLE TIME IN CYCLE DISTRIBUTION /USAGE POINT MICROBIAL PYROGEN , pH DAIILY 25

Validation Of Utilities:

Validation Of Utilities 1.VALIDATION OF GASES : nitrogen, carbon dioxide, compressed air. VALIDATION OF GASES INCLUDES 3 STEPS Supply of gas (adequate purity & quality) Storage conditions Distribution network 26

Validation Of Utilities:

Validation Of Utilities 2. Validation of steam system validation of steam generator Efficiency. Pressure. Analysis of condensate. Distribution network . 3. Validation of electrical system main objective is to meet : Qualitative specifications. ( frequency, voltage, stability ). Quantitative specifications ( load demand ). Back up system are validated . 27

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VALIDATION OF FILLING Parenterals are checked for Fill volume Syringe able volume Sterile filling Monitoring of viable &non viable particles: Particle counter Strip test Reuter centrifugal sample (RCS ) 28

Key Terms In Sterilization :

Key Terms In Sterilization D-value : time required to reduce the microbial content by 90%i.e.one logarithmic reduction F-value: time required to destroyed all spores of suspension when using a suspension at 121 °c Z-value: the no of degree required for 1 log reduction in D-value N 0 –value: No of living organism / defined unit of surface Log reduction value : ability of filter in terms of log reduction of microbial population. 29

Validation Of Sterilization :

Validation Of Sterilization Biological indicator E.g. for steam sterilization-Bacillus stearothermophillus for dry heat sterilization- Bacillus subtilis var. niger for ethylene oxide- Bacillus subtilis var. globigli for ionizing radiation- bacillus pumilis 30

Validation Of Moist Heat Sterilization :

Validation Of Moist Heat Sterilization Operation condition are 121 ºc, 15Psig, for 20 min 1. Qualification & calibration: Checking, upgrading the unit 2. Selection & calibration of thermocouples 3. Selection & calibration of B.I 4. Heat distribution studies 1. cool spot is find out 2. temp dif should not be more than + 2.5 ºc 5. Heat penetration studies By container mapping studies- in which thermocouples are introduced at different heights in the container. 31

Validation of dry heat sterilization :

Validation of dry heat sterilization Its done for Batch oven & tunnel oven validation mainly includes Qualification & calibration Selection & calibration of thermocouples Selection & calibration of B.I Air balance determination 5. Heat distribution studies 1. cool spot is find out 2. temp dif should not be more than + 2.5 ºc 6. Heat penetration studies 32

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Validation of radiation sterilization Major source are cobalt 60 , ceasium 136 . Determine D-values using biological indicator. First calculation of dose based on bio –burden. Calibration of equipment so that same amount of radiation is released every time. Normal dose for over kill approach is 2.5 Mrad . 33

Validation Of Sanitization :

Validation Of Sanitization Sources for contamination are Skin &hair fragments. Droplets from mucous membrane. Material deposition due to personal. Fibers released from person &equipment. Packaging material. so to maintain aseptic conditions we need something other thsn hepa filters i.e. SANITIZER Def- it is defined as a chemical agent that kills microbial contamination in the vegetative form only. E.g.; Hypochlorite , phenol ,surfactant etc. 34

VALIDATION OF FILTRATION :

VALIDATION OF FILTRATION Membrane filters are cartridges & plates Physical integrity of filter media is checked by Bubble point test. Bacterial challenge test. Flow rate. Longevity of filter . 35

VALIDATION OF PACKAGING:

VALIDATION OF PACKAGING a) INTEGRITY OF RUBBER : Quality Penetratability Fragmentation Water extractive Self-seal ability b) INTEGRITY OF GLASS : There are mainly 4 types of glass TYPE I (borosilicate glass ). For ( parenterals ) TYPE II ( treated soda lime glass). (for dry powders) TYPE III (soda lime glass). TYPE IV (non parenteral glass) 36

MOST COMMON TESTS PERFORMED ARE ::

MOST COMMON TESTS PERFORMED ARE : Chemical composition Leaching Powder glass test Water attack test C) Leaking tests: There are mainly two types of leak test: Vacuum dye leak test. Autoclave dye test. 37

VALIDATION OF SOLID DOSAGE FORM :

VALIDATION OF SOLID DOSAGE FORM Validation is a systematic approach to identifying, measuring, evaluating ,documenting,& reevaluating a series of critical steps in manufacturing process that require control to ensure are producible final product. 38

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Key elements that form the basis of a prospective process validation program Definition of the desirable attributes of drug product or components thereof as well as those characteristics that are not desired 2. Establishment of limitation or constraints for these attributes 3. Determination of the controls or testing parameters that will be measured or tested. 4. Initiation of studies to establish control or boundary limits for those attributes that influence the product, process ,quality & performance. 39

VALIDATION OF RAW MATERIAL :

VALIDATION OF RAW MATERIAL It includes validation of both active ingredients& excipients . Characteristics particle size, surface area, color, density. Chemical characteristics- water content residue on ignition & heavy metals. Variables: Flow, blend uniformity, granulation solution/binder uptake compressibility ,lubricant efficiency eg;1) Mg sterate (lubricant). Its action depends on particle size. 2) dyes (color) variation in material occur depending up on …. a) Method of transportation chosen, b) Exposure of material to undesirable conditions (heat and humidity) 40

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Steps involved in validation of raw materials Each raw material should be validated by performing checks on several batches, preferably 3,from the primary supplier as well as the alternate supplier .the batches chosen should be selected to represent the range of acceptable specifications both high and low 2. Depending on susceptibility of the raw material to ageing ,either physical , chemical or microbial stability assessed . 41

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Once the samples of raw materials have been selected it should be used to manufacture a batch of final dosage form it may be appropriate to manufacture to several lots of final product with raw material at the low &high ends of the specifications limit . The final step of raw material should involve an on –site inspection of the supplier to review the vendors manufacturing operations and control procedures 42

ANALYTICAL METHODS OF VALIDATION:

ANALYTICAL METHODS OF VALIDATION Analytical criteria must be assessed ………. Accuracy of method Precision of method In –day /out –of-day variation Operator variation. Instrument variation Laboratory variation 43

DEFINATION &CONTROL OF PROCESS VARIABLES:

DEFINATION &CONTROL OF PROCESS VARIABLES process validation can be defined as means of challenging a process during development to determine which variables must be controlled to ensure consistent production of a product or intermediate. Steps in development of validation program : Obtaining test data to determine the numerical range of each parameter E.g.: assess the tablet hardness over a series of batches . Establishing specification limits from the test data derived for a given parameter. Determining how well the specification limit indicates that the process is under control Certify the equipment operating conditions Eg : rpm , temp, are within specification limits. 44

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General tests in process validation are Moisture content Content uniformity Hardness Disintegration & dissolution Friability Weight variation Granulation particle size distribution 45

Guidelines for process validation :

Guidelines for process validation Tablet composition: Normal properties Density Particle size distribution Surface area Flow properties Moisture content solubility 46

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B. Process evaluation & selection : Blending operation Determine time of un mixing Characteristics of blend bulk density Particle size distribution Color uniformity C. Wet granulation 1.Evaluation of binder Binder concentration Solubility in granulating solution 2.Evalution of mixed granulation 3.Evalution of drying 47

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4. Tablet compression Appearance Color quality Power flow Speed of tablet machine 5.Tablet coating Evaluate coating procedure in different size pans Coating speed Amount of material required / application 48

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D. Equipment evaluation Blending equipment Granulating equipment Tablet equipment Tablet coating. 49

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References Pharmaceutical dosage forms: parenterals medications vol III LACHMAN LEBERMANN PHARMACEUTICAL PROCESS VALIDATION BERRY & NASH Validation of aseptic pharmaceutical process J.P.AGALLOCCO CARLETON WWW.GOOGLE.CO.IN . 50

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